NMR SPECTROSCOPIC EVIDENCE AND MOLECULAR-DYNAMICS STUDIES ON INCLUSION AND NONINCLUSION PHENOMENA BETWEEN BETA-CYCLODEXTRIN AND NEW ANTI-ALZHEIMERS DRUGS TACRINE (CI-970), VELNACRINE (HP-029) AND SURONACRINE (HP-128)

The formation of supramolecular complexes of beta-CD with new generati on anti-Alzheimer's agents of the 1,2,3,4-tetrahydro-9-aminoacridine f amily (tacrine hydrochloride, 1, velnacrine maleate, 2 and suronacrine maleate, 3), has been studied using molecular dynamics (MD) simulatio ns both in vacuo and with a water sphere, High-field NMR experiments f or 1 and 2 gave experimental evidence of their effective non-inclusion . However, earlier NMR studies demonstrated inclusion of 3 on the basi s of the observed upheld shifts of the 3-H and 5-H protons of the beta -CD cavity, MD calculations performed for molecules in vacuo gave unce rtain results that evidenced failure of this model to reproduce consis tently the set of the three experiments, such a failure was overcome b y including explicitly water molecules in the model, thus showing that an oversimplified model for modelling complexes of charged molecules is susceptible to incorrect conclusions. The calculations performed fo r cations 1, 2 and 3 in the water sphere alsb showed that 1 and 2 are more hydrophilic than 3, This suggests that the relative strength of t he solvation and of the complex formation constants favours complexati on of 3 instead of its non-inclusion, and vice versa in the cases of 1 and 2. An important general aspect of beta-CD supramolecular complexe s of charged species was found to be controlled by the solvation effec ts that must be necessarily included to correctly model, in the absenc e of safe experimental information like that coming from NMR, inclusio n or non-inclusion of a guest into the host.